RESUMO
Cancer represents one of the most significant health challenges currently facing humanity, and plant-derived antitumour drugs represent a prominent class of anticancer medications in clinical practice. Isovaleryl sucrose esters, which are natural constituents, have been identified as having potential antitumour effects. However, the mechanism of action remains unclear. In this study, 12 isovaleryl sucrose ester components, including five new (1-5) and seven known compounds (6-12), were isolated from the roots of Atractylodes japonica. The structures of the compounds were elucidated using 1D and 2D-NMR spectroscopy, complemented by HR-ESI-MS mass spectrometry. The cytotoxic activities of all the compounds against human colon cancer cells (HCT-116) and human lung adenocarcinoma cells (A549) were also evaluated using the CCK8 assay. The results demonstrated that compounds 2, 4, and 6 were moderately inhibitory to HCT-116 cells, with IC50 values of 7.49 ± 0.48, 9.03 ± 0.21, and 13.49 ± 1.45 µM, respectively. Compounds 1 and 6 were moderately inhibitory to A549, with IC50 values of 8.36 ± 0.77 and 7.10 ± 0.52 µM, respectively. Molecular docking revealed that compounds 1-9 exhibited a stronger affinity for FGFR3 and BRAF, with binding energies below -7 kcal/mol. Compound 2 exhibited the lowest binding energy of -10.63 kcal/mol to FGFR3. We screened the compounds with lower binding energies, and the protein-ligand complexes already obtained after molecular docking were subjected to exhaustive molecular dynamics simulation experiments, which simulated the dynamic behaviour of the molecules in close proximity to the actual biological environment, thus providing a deeper understanding of their functions and interaction mechanisms. The present study provides a reference for the development and use of iso-valeryl sucrose esters in the antitumour field.
Assuntos
Atractylodes , Ésteres , Simulação de Acoplamento Molecular , Sacarose , Humanos , Sacarose/química , Sacarose/análogos & derivados , Sacarose/farmacologia , Ésteres/química , Ésteres/farmacologia , Atractylodes/química , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Células HCT116 , Linhagem Celular Tumoral , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células A549 , Simulação de Dinâmica Molecular , Proliferação de Células/efeitos dos fármacosRESUMO
Purpose: Traditional Chinese medicine (TCM) therapy is an important means to treat hepatocellular carcinoma (HCC), Astragalus (Latin name: Hedysarum Multijugum Maxim; Chinese name: Huangqi, HQ) and Atractylodes (Latin name: Atractylodes Macrocephala Koidz; Chinese name: Baizhu, BZ) (HQBZ), a classic herb pair, is often used in combination to HCC. However, the main components and potential mechanisms of HQBZ therapy in HCC remain unclear. This study aimed to identify the potential active ingredients and molecular mechanisms of action of HQBZ in HCC treatment. Methods: The HQBZ-Compound-Target-HCC network and HQBZ-HCC transcriptional regulatory network were constructed to screen the core active compound components and targets of HQBZ therapy for HCC. Molecular docking techniques are used to verify the stability of binding core active compound components to targets. GO and KEGG enrichment analysis were used to explore the signaling pathway of HQBZ in HCC treatment, the mechanism of HQBZ treatment of HCC was verified based on in vivo H22 tumor bearing mice and in vitro cell experiments. Results: Network pharmacology and molecular docking studies showed that HQBZ treatment of HCC was related to the targeted regulation of IL-6 and STAT3 by the active compound biatractylolide, KEGG pathway enrichment analysis suggest that HQBZ may play a role in the treatment of HCC through IL-6/STAT3 signaling pathway. In vitro experiment results proved that HQBZ could regulate IL-6/STAT3 signaling pathway transduction on CD8+T cells, inhibit CD8+T cell exhaustion and restore the function of exhausted CD8+T cells. In vivo experiment results proved that HQBZ can regulate IL-6/STAT3 signaling pathway transduction in H22 liver cancer model mouse tumor tissue, increased the proportion of tumor infiltrating CD8+T cells. Conclusion: This study found that HQBZ may play a therapeutic role in HCC by targeting IL-6 and STAT3 through biatractylolide, its mechanism of action is related to regulating IL-6/STAT3 signaling pathway, reversing T cell failure and increasing tumor infiltration CD8+T cells.
Assuntos
Antineoplásicos Fitogênicos , Atractylodes , Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Farmacologia em Rede , Fator de Transcrição STAT3 , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Humanos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Camundongos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Atractylodes/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Simulação de Acoplamento Molecular , Astrágalo/química , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/metabolismo , Interleucina-6/metabolismo , Interleucina-6/antagonistas & inibidores , Medicina Tradicional Chinesa , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Atractylodes macrocephala Koidz, a traditional Chinese medicine, contains atractylenolide I (ATR-I), which has potential anticancer, anti-inflammatory, and immune-modulating properties. This study evaluated the therapeutic potential of ATR-I for indomethacin (IND)-induced gastric mucosal lesions and its underlying mechanisms. Noticeable improvements were observed in the histological morphology and ultrastructures of the rat gastric mucosa after ATR-I treatment. There was improved blood flow, a significant decrease in the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, and IL-18, and a marked increase in prostaglandin E2 (PGE2) expression in ATR-I-treated rats. Furthermore, there was a significant decrease in the mRNA and protein expression levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), and nuclear factor-κB (NF-κB) in rats treated with ATR-I. The results show that ATR-I inhibits the NLRP3 inflammasome signaling pathway and effectively alleviates local inflammation, thereby improving the therapeutic outcomes against IND-induced gastric ulcers in rats.
Assuntos
Atractylodes , Mucosa Gástrica , Indometacina , Inflamassomos , Lactonas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Sesquiterpenos , Úlcera Gástrica , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Indometacina/efeitos adversos , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Ratos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Lactonas/farmacologia , Lactonas/química , Inflamassomos/metabolismo , Inflamassomos/genética , Inflamassomos/efeitos dos fármacos , Masculino , Atractylodes/química , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , NF-kappa B/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/imunologia , Caspase 1/genética , Caspase 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-6/imunologia , Interleucina-18/genética , Interleucina-18/metabolismoRESUMO
Atractylodis rhizoma is a common bulk medicinal material with multiple species. Although different varieties of atractylodis rhizoma exhibit variations in their chemical constituents and pharmacological activities, they have not been adequately distinguished due to their similar morphological features. Hence, the purpose of this research is to analyze and characterize the volatile organic compounds (VOCs) in samples of atractylodis rhizoma using multiple techniques and to identify the key differential VOCs among different varieties of atractylodis rhizoma for effective discrimination. The identification of VOCs was carried out using headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) and headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS), resulting in the identification of 60 and 53 VOCs, respectively. The orthogonal partial least squares discriminant analysis (OPLS-DA) model was employed to screen potential biomarkers and based on the variable importance in projection (VIP ≥ 1.2), 24 VOCs were identified as critical differential compounds. Random forest (RF), K-nearest neighbor (KNN) and back propagation neural network based on genetic algorithm (GA-BPNN) models based on potential volatile markers realized the greater than 90 % discriminant accuracies, which indicates that the obtained key differential VOCs are reliable. At the same time, the aroma characteristics of atractylodis rhizoma were also analyzed by ultra-fast gas chromatography electronic nose (Ultra-fast GC E-nose). This study indicated that the integration of HS-SPME-GC-MS, HS-GC-IMS and ultra-fast GC E-nose with chemometrics can comprehensively reflect the differences of VOCs in atractylodis rhizoma samples from different varieties, which will be a prospective tool for variety discrimination of atractylodis rhizoma.
Assuntos
Atractylodes , Nariz Eletrônico , Cromatografia Gasosa-Espectrometria de Massas , Microextração em Fase Sólida , Compostos Orgânicos Voláteis , Compostos Orgânicos Voláteis/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Microextração em Fase Sólida/métodos , Atractylodes/química , Espectrometria de Mobilidade Iônica/métodos , Rizoma/química , Análise DiscriminanteRESUMO
ß-Elemene, an important component of the volatile oil of Atractylodis macrocephala, has been widely utilized as an antitumor drug for over 20 years. However, the germacrene A synthase (GAS) genes responsible for the biosynthesis of ß-elemene in A. macrocephala were previously unidentified. In this study, two new AmGASs were identified from the A. macrocephala transcriptome, demonstrating their capability to convert farnesyl pyrophosphate into germacrene A, which subsequently synthesizes ß-elemene through Cope rearrangement. Additionally, two highly catalytic AmGAS1 mutations, I307A and E392A, resulted in a 2.23-fold and 1.57-fold increase in ß-elemene synthesis, respectively. Furthermore, precursor supply and fed-batch strategies were employed to enhance the precursor supply, resulting in ß-elemene yields of 7.3 mg/L and 33.3 mg/L, respectively. These findings identify a promising candidate GAS for ß-elemene biosynthesis and lay the foundation for further functional studies on terpene synthases in A. macrocephala.
Assuntos
Sesquiterpenos de Germacrano , Sesquiterpenos , Sesquiterpenos/metabolismo , Sesquiterpenos/química , Sesquiterpenos de Germacrano/metabolismo , Alquil e Aril Transferases/metabolismo , Alquil e Aril Transferases/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fosfatos de Poli-Isoprenil/metabolismo , Atractylodes/metabolismo , Atractylodes/química , Atractylodes/genética , Vias Biossintéticas , TranscriptomaRESUMO
Atractylodes macrocephala Koidz (AMK) is a traditional herbal medicine used for thousands of years in East Asia to improve a variety of illnesses and conditions, including cancers. This study explored the effect of AMK extract on apoptosis and tumor-grafted mice using AGS human gastric adenocarcinoma cells. We investigated the compounds, target genes, and associated diseases of AMK using the Traditional Chinese Medical Systems Pharmacy (TCMSP) database platform. Cell viability assay, cell cycle and mitochondrial depolarization analysis, caspase activity assay, reactive oxygen species (ROS) assay, and wound healing and spheroid formation assay were used to investigate the anti-cancer effects of AMK extract on AGS cells. Also, in vivo studies were conducted using subcutaneous xenografts. AMK extract reduced the viability of AGS cells and increased the sub-G1 cell fraction and the mitochondrial membrane potential. Also, AMK extract increased the production of ROS. AMK extract induced the increased caspase activities and modulated the mitogen-activated protein kinases (MAPK). In addition, AMK extract effectively inhibited AGS cell migration and led to a notable reduction in the growth of AGS spheroids. Moreover, AMK extract hindered the growth of AGS xenograft tumors in NSG mice. Our results suggest that AMK has anti-cancer effects by promoting cell cycle arrest and inhibiting the proliferation of AGS cancer cells and a xenograft model through apoptosis. This study could provide a novel approach to treat gastric cancer.
Assuntos
Atractylodes , Neoplasias Gástricas , Humanos , Animais , Camundongos , Neoplasias Gástricas/tratamento farmacológico , Espécies Reativas de Oxigênio , Caspases , Extratos Vegetais/farmacologiaRESUMO
Two new sesterterpenoids, atractylodes japonica terpenoid acid I (1) and atractylodes japonica terpenoid aldehyde I (2), were isolated from the rhizomes of Atractylodes japonica Koidz. ex Kitam together with ten known compounds (3-12). Their structures were elucidated on the basis of comprehensive spectroscopic analysis (1D/2D NMR, HRESIMS and IR). In addition, all of these isolated compounds were evaluated for their cytotoxic activities against human gastric cancer cell MGC-803 and human hepatocellular cancer cell HepG-2. Most of them exhibited moderate to weak inhibitory effects with IC50 values in the range of 25.15-88.85 µM except for 9-12.
Assuntos
Atractylodes , Rizoma , Sesterterpenos , Atractylodes/química , Humanos , Estrutura Molecular , Linhagem Celular Tumoral , Sesterterpenos/química , Sesterterpenos/farmacologia , Sesterterpenos/isolamento & purificação , Rizoma/química , Células Hep G2 , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
The rhizomes of the genus Atractylodes DC. consist of various bioactive components, including sesquiterpenes, which have attracted a great deal of research interest in recent years. In the present study, we reviewed the previously published literatures prior to November 2023 on the chemical structures, biosynthetic pathways, and pharmacological activities of the sesquiterpenoids from this genus via online databases such as Web of Science, Google Scholar, and ScienceDirect. Phytochemical studies have led to the identification of more than 160 sesquiterpenes, notably eudesmane-type sesquiterpenes. Many pharmacological activities have been demonstrated, particularly anticancer, anti-inflammatory, and antibacterial and antiviral activities. This review presents updated, comprehensive and categorized information on the phytochemistry and pharmacology of sesquiterpenes in Atractylodes DC., with the aim of offering guidance for the future exploitation and utilization of active ingredients in this genus.
Assuntos
Atractylodes , Sesquiterpenos de Eudesmano , Sesquiterpenos , Atractylodes/química , Rizoma/química , Sesquiterpenos/química , Sesquiterpenos de Eudesmano/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/análise , Etnofarmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/análise , FitoterapiaRESUMO
Atractylodes macrocephala III (ATL III), with anti-inflammatory and antitumor effects, is the main compound of Atractylodes macrocephala. Whether ATL III has an effect on cervical cancer and the specific mechanism are still unclear. Here, we investigated the effects of ATL III on cervical cancer cells at different concentrations and found that ATL III downregulates insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), which was found to be highly expressed in cervical cancer tissue by RNA-Seq. In this study, we found that ATL III promotes apoptosis and regulates epithelial-mesenchymal transition (EMT) in cervical cancer cells (HeLa and SiHa cells) and that IGF2BP3 is a common target gene of ATL III in HeLa and SiHa cells. The expression level of IGF2BP3 in cervical cancer cells was proportional to their migration and invasion abilities. This was verified by transfection of cells with a small interfering RNA and an IGF2BP3 overexpression plasmid. After ATL III treatment, the migration and invasion abilities of cervical cancer cells were obviously reduced, but these effects were attenuated after overexpression of IGF2BP3. In addition, the transcription factor IGF2BP3 was predicted by the JASPAR system. After intersection with our sequencing results, we verified the promotional effect of ETV5 (ETS translocation variant 5) on IGF2BP3 and found that ALT III inhibited ETV5. In general, our research showed that ATL III inhibits the migration and invasion of cervical cancer cells by regulating IGF2BP3 through ETV5.
Assuntos
Atractylodes , Neoplasias do Colo do Útero , Feminino , Humanos , Atractylodes/química , Neoplasias do Colo do Útero/patologia , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Transição Epitelial-Mesenquimal/genética , Proliferação de Células/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a DNA/genéticaRESUMO
BACKGROUND: A statistical model is essential in determining the appropriate predictive indicators for therapies in many types of cancers. Predictors have been compared favorably to the traditional systems for many cancers. Thus, this study has been proposed as a new standard approach. A recent study on the clinical efficacy of Atractylodes lancea (Thunb) DC. (AL) revealed the higher clinical benefits in patients with advanced-stage intrahepatic cholangiocarcinoma (ICC) treated with AL compared with standard supportive care. We investigated the relationships between clinical efficacy and pharmacokinetic parameters of serum bioactivity of AL and its active constituent atractylodin and determined therapeutic ranges. METHODS: Group 1 of advanced-stage ICC patients received daily doses of 1000 mg of standardized extract of the capsule formulation of AL (CMC-AL) for 90 days. Group 2 received daily doses of 1000 mg of CMC-AL for 14 days, followed by 1500 mg for 14 days, and 2000 mg for 62 days. Group 3 (control group) received palliative care. Cox proportional hazard model and Receiver Operating Characteristic (ROC) were applied to determine the cut-off values of AUC0-inf, Cmax, and Cavg associated with therapeutic outcomes. Number needed to treat (NNT) and relative risk (RR) were also applied to determine potential predictors. RESULTS: The AUC0-inf of total AL bioactivity of >96.71 µg hour/ml was identified as a promising predictor of disease prognosis, that is, progression-free survival (PFS) and disease control rate (DCR). Cmax of total AL bioactivity of >21.42 was identified as a predictor of the prognosis of survival. The therapeutic range of total AL bioactivity for PFS and DCR is 14.48 to 65.8 µg/ml, and for overall survival is 10.97 to 65.8 µg/ml. Conclusions: The predictors of ICC disease prognosis were established based on the pharmacokinetics of total AL bioactivity. The information could be exploited to improve the clinical efficacy of AL in patients with advanced-stage ICC. These predictors will be validated in a phase 2B clinical study. TRIAL REGISTRATION: TCTR20210129007 (TCTR: www.clinicaltrials.in.th).
Assuntos
Atractylodes , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Prognóstico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Extratos Vegetais/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodis Rhizoma is extensively employed in Traditional Chinese Medicine for the treatment of skin and gastrointestinal ailments. Its active components have been proven to demonstrate numerous beneficial properties, including antibacterial, antiviral, anti-inflammatory, anti-tumor, and anti-ulcer activities. Furthermore, the volatile oil from Atractylodis Rhizoma (VOAR) has been reported to effectively inhibit and eradicate pathogens such as Staphylococcus aureus, Escherichia coli and Candida albicans. Of particular concern is Staphylococcus pseudintermedius, the predominant pathogen responsible for canine pyoderma, whose increasing antimicrobial resistance poses a serious public health threat. VOAR merits further investigation regarding its antibacterial potential against Staphylococcus pseudintermedius. AIM OF THE STUDY: The study aims to verify the in vitro antibacterial activity of VOAR against Staphylococcus pseudintermedius. And a superficial skin infection model in mice was established to assess the in vivo therapeutic effect of VOAR. MATERIALS AND METHODS: Thirty strains of S. pseudintermedius were isolated from dogs with pyoderma, and the drug resistance was analyzed by disc diffusion method. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of VOAR were determined through the broth dilution method. The growth curve of bacteria in a culture medium containing VOAR was monitored using a UV spectrophotometer. Scanning electron microscopy was employed to observe the effects of VOAR on the microstructure of S. pseudintermedius. The impact of VOAR on the antibiotic resistance of S. pseudintermedius was assessed using the disc diffusion method. Twenty mice were randomly divided into four groups: the control group, the physiological saline group, the VOAR group, and the amikacin group. With the exception of the control group, the skin barrier of mice was disrupted by tap stripping, and the mice were subsequently inoculated with S. pseudintermedius to establish a superficial skin infection model. The modeled mice were treated with normal saline, VOAR, and amikacin for 5 days. Following the treatment period, the therapeutic effect of each group was evaluated based on the measures of body weight, skin symptoms, tissue bacterial load, tissue IL-6 content, and histopathological changes. RESULTS: The MIC and MBC of VOAR against 30 clinical isolates of S. pseudintermedius were found to be 0.005425% and 0.016875%, respectively. VOAR could exhibit the ability to delay the entry of bacteria into the logarithmic growth phase, disrupt the bacterial structure, and enhance the antibacterial zone in conjunction with antibiotic drugs. In the superficial skin infection model mice, VOAR significantly reduced the scores for skin redness (P < 0.0001), scab formation (P < 0.0001), and wrinkles (P < 0.0001). Moreover, VOAR markedly reduced the bacterial load (P < 0.001) and IL-6 content (P < 0.0001) in the skin tissues of mice. Histopathological observations revealed that the full-layer skin structure in the VOAR group was more complete, with clearer skin layers, and showed significant improvement in inflammatory cell infiltration and fibroblast proliferation compared to other groups. CONCLUSION: The results demonstrate that VOAR effectively inhibits and eradicates Staphylococcus pseudintermedius in vitro while also enhancing the pathogen's sensitivity to antibiotics. Moreover, VOAR exhibits a pronounced therapeutic effect in the superficial skin infection model mice.
Assuntos
Atractylodes , Staphylococcus aureus Resistente à Meticilina , Pioderma , Cães , Animais , Camundongos , Amicacina , Interleucina-6 , Pioderma/tratamento farmacológico , Pioderma/veterinária , Antibacterianos/farmacologiaRESUMO
BACKGROUND: Porcine infection with Porcine circovirus type 2 (PCV2) causes immunosuppression, which is easy to cause concurrent or secondary infection, making the disease complicated and difficult to treat, and causing huge economic losses to the pig industry. Total polysaccharide from the rhizoma of Atractylodes macrocephala Koidz. (PAMK) is outstanding in enhancing non-specific immunity and cellular immunity, and effectively improving the body's disease resistance, indicating its potential role in antiviral immunotherapy. RESULTS: PAMK had the characteristics of compact, polyporous and agglomerated morphology, but does not have triple helix conformation. PCV2 infection led to the increase in LC3-II, degradation of p62 and the increase of viral Cap protein expression and viral copy number. PAMK treatment significantly alleviated PCV2-induced autophagy and inhibited PCV2 replication. Moreover, PAMK treatment significantly attenuated the increase of PINK1 protein expression and the decrease of TOMM20 protein expression caused by PCV2 infection, alleviated Parkin recruitment from cytoplasm to mitochondria and intracellular reactive oxygen species accumulation, restored mitochondrial membrane charge, alleviated viral Cap protein expression. CONCLUSION: PAMK alleviates PCV2-induced mitophagy to suppress PCV2 replication by inhibiting the Pink 1/Parkin pathway. These findings may provide new insights into the prevention and treatment of PCV2. © 2023 Society of Chemical Industry.
Assuntos
Atractylodes , Circovirus , Animais , Suínos , Atractylodes/química , Circovirus/genética , Circovirus/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Polissacarídeos/química , Replicação ViralRESUMO
BACKGROUND: Atractylodes japonica Koidz. ex Kitam. (A. japonica, Chinese name: Guan-Cangzhu, Japanese name: Byaku-jutsu), a perennial herb, which is mainly distributed in northeast area of China, it's often used to treat digestive system diseases such as gastric ulcer (GU). However, the mechanism of its potential protective effects against GU remains unclear. AIM: To investigate the protective effects of A. japonica on acetic acid-induced GU rats. METHODS: The chemical constituents of A. japonica were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analysis. The rat model of GU was simulated by acetic acid method. The pathological changes of gastric tissues were evaluated by hematoxylin-eosin stain, the levels of epidermal growth factor (EGF), EGF receptor (EGFR), nuclear factor kappa-B (NF-κB), interleukin-1ß (IL-1ß), IL-10, Na+-K+-ATPase (NKA) in serum and gastric tissues were determined by enzyme-linked immunosorbent assay, and the mRNA expressions of EGFR, NF-κBp65, IkappaBalpha (IκBα) and Zonula Occludens-1 (ZO-1) in gastric tissues were determined by real-time reverse transcription polymerase chain reaction, and the efficacy was observed. Then, plasma metabolomic analysis was performed by UPLC-MS/MS to screen the specific potential biomarkers, metabolic pathways and to explore the possible mechanisms. RESULTS: 48 chemical constituents were identified. Many of them have strong pharmacological activity, the results also revealed that A. japonica significantly improved the pathological damage of gastric tissues, increased the expression levels of IL-10, IκBα related to anti-inflammatory factors, decreased the expression levels of IL-1ß, NF-κB, NF-κBp65, related to proinflammatory factors, restored the levels of factors about EGF, EGFR, ZO-1 associated with ulcer healing and the levels of factors about NKA associated with energy metabolism. Metabolomic analysis identified 10 potential differential metabolites and enriched 7 related metabolic pathways. CONCLUSION: These findings contribute to the understanding of the potential mechanism of A. japonica to improve acetic acid-induced GU, and will be of great importance for the development and clinical application of natural drugs related to A. japonica.
Assuntos
Atractylodes , Úlcera Gástrica , Ratos , Animais , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/prevenção & controle , Ácido Acético/toxicidade , Atractylodes/química , Atractylodes/metabolismo , NF-kappa B/metabolismo , Interleucina-10 , Inibidor de NF-kappaB alfa , Fator de Crescimento Epidérmico , Cromatografia Líquida , Espectrometria de Massas em Tandem , Receptores ErbBRESUMO
The aim of this study was to conduct a screening of potential therapeutic compounds found in the Atractylodes macrocephala rhizoma essential oil (AO) and explore its mechanism of action in the treatment of ulcerative colitis (UC). An inflammation cell model was employed in conjunction with phospho-antibody array technology to explore potential therapeutic compounds of AO and their anti-inflammatory and antioxidant effects. Furthermore, we assessed their efficacy and mechanisms of action in treating dextran sulfate sodium (DSS)-induced colitis in mice. Via the screening process, we identified atractylone (ATR) as the primary active compound in AO. It has been demonstrated that ATR can both decrease the levels of tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) and increase the expression of adhesion proteins such as claudin, ZO-1, and occludin in vitro. Moreover, ATR has been shown to improve UC symptoms in vivo. Via a non-targeted metabolomics analysis of colon tissue, we identified 57 distinct metabolites that responded to ATR treatment. Subsequent analysis of the metabolic pathways revealed that the action of ATR was primarily focused on the amino acid metabolism pathway. In summary, ATR may alleviate the symptoms of UC by regulating multiple signaling pathways. Additionally, ATR has a comprehensive function in anti-inflammation, antioxidative stress, and intestinal injury reduction.
Assuntos
Atractylodes , Colite Ulcerativa , Colite , Óleos Voláteis , Animais , Camundongos , Atractylodes/química , Óleos Voláteis/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Alcoholic gastric ulcer is a common acute gastric injury disease. The drugs currently used in clinical practice not only cannot fundamentally treat gastric injury, but also have serious side effects. There is an urgent demand for the discovery of a mild drug to treat alcoholic gastric ulcers. Herein, the green carbon dots derived from charred Atractylodes macrocephala (CAM-CDs) were acquired and have been proven to be safe and effective in alleviating alcoholic gastric ulcers at an inhibition rate up to 60%. CAM-CDs can markedly attenuate the gastric mucosa damage such as mucosal defect, bleeding and inflammatory cell infiltration by histopathological examination. Serum and tissue inflammatory cytokine measurements, as well as immunohistochemistry results, indicate that its mechanism of gastric mucosal protection may involve the reduction of IL-1ß and TNF-α by regulating inflammatory signaling pathway of the NF-κB/NLRP3 axis, as well as elevation of IL-10 levels. CAM-CDs also can reduce oxidative stress markers (MDA), increase PGE2 and mucin secretion (MUC5AC), and it simultaneously exerts slight inhibition of hydrogen potassium ATPase and pepsin activity to protect gastric mucosa, as well as increases the microbial diversity and regulates species composition of gut microbiota in rats with gastric ulcer. Our work provides a new perspective on utilizing carbon-based nanomaterials in the development of new mild drugs.
Assuntos
Atractylodes , Nanopartículas , Úlcera Gástrica , Ratos , Animais , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Úlcera Gástrica/prevenção & controle , Atractylodes/química , Atractylodes/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transdução de Sinais , Nanopartículas/uso terapêutico , Mucosa Gástrica/metabolismoRESUMO
BACKGROUND: Cholangiocarcinoma (CCA), the adenocarcinoma of the biliary duct, is commonly reported in Asia, with the highest incidence in northeastern Thailand. Chemotherapy of CCA has been limited by the lack of effective chemotherapeutic drugs. A series of previous in vitro and in vivo studies support further research and development of Atractylodes lancea (Thunb.) DC. (AL) as a potential candidate for treating CCA as a crude ethanolic extract. In the present study, we evaluated the toxicity and anti-CCA activity of the CMC (Chemistry, Manufacturing, and Control) capsule formulation of the ethanolic rhizome extract of AL (CMC-AL) in animals. METHODS: Major steps included acute, subchronic and chronic toxicity testing in Wistar rats and anti-CCA activity in a CCA-xenografted nude mouse model. The safety of CMC-AL was determined based on the maximum tolerated dose (MTD) and no-observed-adverse-effect level (NOAEL) according to the OECD guideline. The anti-CCA activity of CMC-AL in nude mice was evaluated after transplantation of CL-6 cells to evaluate inhibitory effects on tumor size progression and metastasis and survival time prolongation. Safety assessments included hematology, biochemistry parameters and histopathological examination. Lung metastasis was investigated using VEGF ELISA kit. RESULTS: All evaluations confirmed satisfactory pharmaceutical properties of oral formulation and safety profile of the CMC-AL with no overt toxicity up to the MTD and NOAEL of 5,000 and 3,000 mg/kg body weight, respectively. CMC-AL exhibited potent anti-CCA efficacy with regard to inhibitory activity on tumor progression and lung metastasis. CONCLUSIONS: CMC-AL is safe and should be further investigated in a clinical trial as a potential therapy for CCA patients.
Assuntos
Atractylodes , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Ratos , Camundongos , Animais , Atractylodes/química , Camundongos Nus , Ratos Wistar , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/induzido quimicamente , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/induzido quimicamente , Neoplasias dos Ductos Biliares/patologia , Extratos Vegetais/uso terapêutico , PesquisaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The root of Atractylodes macrocephala Koidz. (AM) has been used for thousands of years in China, and it's extracts contain various constituents, such as volatile oils, polysaccharides, and lactones, with a myriad of pharmacological effects, including improves the healthy state of the gastrointestinal system and regulating immunity, hormone secretion, anti-inflammatory, antibacterial, antioxidation, anti-aging, and antitumor properties. Recently, researchers have focused on the effect of AM in regulating bone mass; therefore, its potential mechanism of action in regulating bone mass needs to be elucidated. AIM OF REVIEW: This study reviewed the known and possible mechanisms of bone mass regulation by AM. MATERIALS AND METHODS: Cochrane, Medline via PubMed, Embase, CENTRAL, CINAHL, Web of Science, Chinese biomedical literature database, Chinese Science and Technology Periodical Database, and Wanfang Database were used to search AM root extracts-related studies. The retrieval date was from the establishment of the database to January 1, 2023. RESULTS: By summarizing 119 natural active substances that have been isolated from AM root to date, we explored its possible targets and pathways (such as Hedgehog, Wnt/ß-catenin, and BMP/Smads pathways etc.) for bone growth and presented our position on possible future research/perspectives in the regulation of bone mass using this plant. CONCLUSIONS: AM root extracts (incuding aqueous, ethanol etc.) promotes osteogenesis and inhibits osteoclastogenesis. These functions promote the absorption of nutrients, regulate gastrointestinal motility and intestinal microbial ecology, regulate endocrine function, strengthen bone immunity, and exert anti-inflammatory and antioxidant effects.
Assuntos
Atractylodes , Óleos Voláteis , China , Extratos Vegetais/farmacologia , Anti-Inflamatórios/farmacologiaRESUMO
Background: Atractylodes macrocephala Koidz. (AM) is a functional food with strong ant-colitis activity. AM volatile oil (AVO) is the main active ingredient of AM. However, no study has investigated the improvement effect of AVO on ulcerative colitis (UC) and the bioactivity mechanism also remains unknown. Here, we investigated whether AVO has ameliorative activity on acute colitis mice and its mechanism from the perspective of gut microbiota. Methods: Acute UC was induced in C57BL/6 mice by dextran sulfate sodium and treated with the AVO. Body weight, colon length, colon tissue pathology, and so on were assessed. The gut microbiota composition was profiled using 16s rRNA sequencing and global metabolomic profiling of the feces was performed. The results showed that AVO can alleviate bloody diarrhea, colon damage, and colon inflammation in colitis mice. In addition, AVO decreased potentially harmful bacteria (Turicibacter, Parasutterella, and Erysipelatoclostridium) and enriched potentially beneficial bacteria (Enterorhabdus, Parvibacter, and Akkermansia). Metabolomics disclosed that AVO altered gut microbiota metabolism by regulating 56 gut microbiota metabolites involved in 102 KEGG pathways. Among these KEGG pathways, many metabolism pathways play an important role in maintaining intestine homeostasis, such as amino acid metabolism (especially tryptophan metabolism), bile acids metabolism, and retinol metabolism. Conclusion: In conclusion, our study indicated that AVO can be expected as novel prebiotics to treat ulcerative colitis, and modulating the composition and metabolism of gut microbiota may be its pharmacological mechanism.
Assuntos
Actinobacteria , Atractylodes , Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Animais , Camundongos , Camundongos Endogâmicos C57BL , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , RNA Ribossômico 16SRESUMO
Atractylenolides, comprising atractylenolide I, II, and III, represent the principal bioactive constituents of Atractylodes macrocephala, a traditional Chinese medicine. These compounds exhibit a diverse array of pharmacological properties, including anti-inflammatory, anti-cancer, and organ-protective effects, underscoring their potential for future research and development. Recent investigations have demonstrated that the anti-cancer activity of the three atractylenolides can be attributed to their influence on the JAK2/STAT3 signaling pathway. Additionally, the TLR4/NF-κB, PI3K/Akt, and MAPK signaling pathways primarily mediate the anti-inflammatory effects of these compounds. Atractylenolides can protect multiple organs by modulating oxidative stress, attenuating the inflammatory response, activating anti-apoptotic signaling pathways, and inhibiting cell apoptosis. These protective effects extend to the heart, liver, lung, kidney, stomach, intestine, and nervous system. Consequently, atractylenolides may emerge as clinically relevant multi-organ protective agents in the future. Notably, the pharmacological activities of the three atractylenolides differ. Atractylenolide I and III demonstrate potent anti-inflammatory and organ-protective properties, whereas the effects of atractylenolide II are infrequently reported. This review systematically examines the literature on atractylenolides published in recent years, with a primary emphasis on their pharmacological properties, in order to inform future development and application efforts.
Assuntos
Atractylodes , Fosfatidilinositol 3-Quinases , Medicina Tradicional Chinesa , Transdução de Sinais , Atractylodes/química , Anti-Inflamatórios/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Alisma and Atractylodes (AA), a classical traditional Chinese herbal decoction, may protect against cerebral ischaemia/reperfusion injury (CIRI). However, the underlying mechanism has not been characterized. Intriguingly, exosomal microRNAs (miRNAs) have been recognized as vital factors in the pharmacology of Chinese herbal decoctions. AIM OF THE STUDY: The aim of the present study was to assess whether the neuroprotective effect of AA was dependent on the efficient transfer of miRNAs via exosomes in the brain. MATERIALS AND METHODS: Bilateral common carotid artery ligation (BCAL) was used to induce transient global cerebral ischaemia/reperfusion (GCI/R) in C57BL/6 mice treated with/without AA. Neurological deficits were assessed with the modified neurological severity score (mNSS) and Morris water maze (MWM) test. Western blot (WB) analysis was used to detect the expression of sirtuin 1 (SIRT1) in the cerebral cortex. The inflammatory state was quantitatively evaluated by measuring the expression of phospho-Nuclear factor kappa B (p-NF-κB), Interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) using WB analysis and glial fibrillary acidic protein (GFAP) immunohistochemical staining. The protein expression of zonula occluden-1 (ZO-1), occludin, caudin-5 and CD31 was examined by immunohistochemical staining to determine bloodâbrain barrier (BBB) permeability. Exosomes were extracted from the brain interstitial space by ultracentrifugation and identified by transmission electron microscopy (TEM), WB analysis and nanoparticle tracking analysis (NTA). The origin of exosomes was clarified by measuring the specific mRNAs within exosomes via Real Time Quantitative PCR (RTâqPCR). Differential miRNAs in exosomes were identified using microarray screening and were validated by RTâqPCR. Exosomes were labelled with fluorescent dye (PKH26) and incubated with bEnd.3 cells, the supernatant was collected, IL-1ß/TNF-α expression was measured using enzyme-linked immunosorbent assay (ELISA), total RNA was extracted, and miR-200a-3p/141-3p expression was examined by RTâqPCR. In addition, the levels of miR-200a-3p/141-3p in oxygen glucose deprivation/reoxygenation (OGD/R)-induced bEnd.3 cells were quantified. The direct interaction between miR-200a-3p/141-3p and the SIRT1 3' untranslated region (3'UTR) was measured by determining SIRT1 expression in bEnd.3 cells transfected with the miR-200a-3p/141-3p mimic/inhibitor. RESULTS: Severe neurological deficits and memory loss caused by GCI/R in mice was markedly ameliorated by AA treatment, particularly in the AA medium-dose group. Moreover, AA-treated GCI/R-induced mice showed significant increases in SIRT1, ZO-1, occludin, caudin-5, and CD31 expression levels and decreases in p-NF-κB, IL-1ß, TNF-α, and GFAP expression levels compared with those in untreated GCI/R-induced mice. Furthermore, we found that miR-200a-3p/141-3p was enriched in astrocyte-derived exosomes from GCI/R-induced mice and could be inhibited by treatment with a medium dose of AA. The exosomes mediated the transfer of miR-200a-3p/141-3p into bEnd.3 cells, promoted IL-1ß and TNF-α release and downregulated the expression of SIRT1. No significant changes in the levels of miR-200a-3p/141-3p were observed in OGD/R-induced bEnd.3 cells. The miR-200a-3p/141-3p mimic/inhibitor decreased/increased SIRT1 expression in bEnd.3 cells, respectively. CONCLUSION: Our findings demonstrated that AA attenuated inflammation-mediated CIRI by inhibiting astrocyte-derived exosomal miR-200a-3p/141-3p by targeting the SIRT1 gene, which provided further evidence and identified a novel regulatory mechanism for the neuroprotective effects of AA.